Cancer is the second leading cause of death in the United States, exceeded only by heart disease. Drugs currently used to treat cancer tend to be toxic at their therapeutic dose levels, commonly causing severe and even life-threatening adverse effects. These adverse effects include serious disorders of the blood, gastrointestinal tract, liver, kidneys, and other organs. Most current anticancer drugs thus have a narrow therapeutic window: the range between the therapeutic dose and the maximum tolerated dose is very small. Due to this toxicity, as well as the fact that most anticancer drugs are administered intravenously, nearly all cancer chemotherapy must be administered in a hospital or clinic. An additional problem with most current cancer chemotherapy is that cancers frequently develop resistance to the drugs, so that recurrence of disease is common.
It is therefore of utmost importance to develop new anticancer agents that are effective in treating drug-resistant cancers, exhibit low toxicity, and have a wide therapeutic window, such that an agent targets diseased tissue while sparing healthy tissue. An ideal anticancer agent would also be easily administrable outside of a clinical setting; orally active compounds would be particularly attractive in this regard. Ideal agents would also be useful prophylactically in patients at risk of developing cancer, in addition to their utility in therapeutic methods. Angiogenesis, the process by which new blood vessels are formed, is essential for many normal physiologic functions, including growth, establishment of the placenta, and wound repair. It is also essential for the growth of cancerous tumors larger than about two mm in diameter (Weidner et al. (1991) New England J. Med. 324:1-8). To obtain sufficient nutrients and oxygen, tumors secrete factors that induce the development of new blood vessels that connect the tumor to the surrounding tissue. Once a tumor establishes a system of blood vessels connected to the host organism, a means is provided by which tumor cells can enter the circulation and metastasize to distant sites such as the liver, lung, or bone. If this neovascularization is prevented or destroyed, the tumor will eventually shrink and die. Some of the most promising anticancer compounds in development are antiangiogenic. These compounds include: angiostatin, a polypeptide of approximately 200 amino acids produced by the cleavage of plasminogen, a plasma protein involved in dissolving blood clots; endostatin, a polypeptide of 184 amino acids that is the globular domain found at the C-terminal of Type 18 collagen, a collagen found in blood vessels; and troponin I, a protein found in muscles. Another antiangiogenic compound in development is a monoclonal antibody directed against the vascular integrin anb3. Other experimental compounds are targeted against VEGF. As all of these compounds in development are proteins, they cannot be administered orally, and they may induce allergic reactions. An additional experimental antiangiogenic compound, suramin, has such high systemic toxicity that its utility is severely limited.
Many diseases other than cancer are also associated with pathologic angiogenesis. Ocular neovascularization has been implicated as the most common cause of blindness. In diabetic retinopathy, capillaries formed in the retina invade the vitreous, bleed, and cause gradual loss of vision leading to blindness. In arthritis, newly formed capillaries and other blood vessels invade the joints and destroy cartilage. In psoriasis, angiogenesis is required to maintain the rapid growth and turnover of skin cells. Many other examples of inflammatory disorders and other diseases associated with angiogenesis are known in the art.
Although some antiangiogenic agents are quite active, many of the currently known agents are associated with a number of problems. For example, many of the known antiangiogenic agents exhibit poor bioavailability, result in numerous side effects, have problems with stability, and are difficult to synthesize in an efficient manner.
Endothelial cell proliferation is a key process in angiogenesis. Endothelial cells form the endothelium—a thin layer of cells that lines blood vessels. Angiogenesis relies on the ability of endothelial cells to proliferate in order to form the endothelium of the newly forming vessels. Thus, while the proliferation of endothelial cells is required for normal physiological processes, angiogenesis associated with the growth of a tumor involves the unwanted proliferation of endothelial cells.
Angiogenesis also requires migration of endothelial cells, for example through the extracellular matrix. Cellular migration is undesirable in the context of metastasis and tumor cells; endothelial cell migration is similarly undesirable in the context of pathologic angiogenesis. The migration of endothelial cells is aided by matrix metalloproteinases, which are involved in the degradation of the extracellular matrix. Importantly, the migration of tumor cells is also aided by matrix metalloproteinases. Thus, the inhibition of matrix metalloproteinases represents a potential method for interrupting metastasis.
Methods of treatment which disrupt unwanted proliferation of endothelial cells and/or unwanted migration of tumor cells and/or endothelial cells would be expected to have value in the treatment of angiogenesis, but would also be expected to have value in the treatment of disease processes besides angiogenesis, especially metastasis. Such methods are therefore desirable independently of how effective they are against angiogenesis.